CN1035552C - Branched alkylamino derivatives of thiazole, processes for preparing them and pharmaceutical compositions containing them - Google Patents

Branched alkylamino derivatives of thiazole, processes for preparing them and pharmaceutical compositions containing them Download PDF

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CN1035552C
CN1035552C CN93109438A CN93109438A CN1035552C CN 1035552 C CN1035552 C CN 1035552C CN 93109438 A CN93109438 A CN 93109438A CN 93109438 A CN93109438 A CN 93109438A CN 1035552 C CN1035552 C CN 1035552C
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G·考特曼切
C·高蒂尔
D·古利
P·罗根
G·瓦莱特
C·G·沃马思
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Sanofi Aventis France
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention relates to the compounds of formula I: in which, R1 represents a phenyl or naphthyl radical (optionally substituted), R2 represents a hydrogen or halogen atom or an alkyl, hydroxymethyl or formyl radical, R3 represents an alkyl, cycloalkyl, alkenyl, cycloalkyalkyl or phenyl radical, R4 represents a hydrogen atom or an alkyl, cycloalkyl or cycloalkylalkyl radical, R5 represents an alkyl, cycloalkyl, cycloalkylalkyl or alkenyl radical or a radical of formula B: (p = 0, 1, 2 or 3), - R6 represents an optionally substituted phenyl, pyridyl, imidazolyl, pyrrolyl, thienyl or furyl radical or a cycloalkyl radical, - m and n, which are identical or different, each represent 0 or 1, their possible stereoisomers and their addition salts.

Description

The branched alkylamino derivatives of thiazole, their preparation method and the pharmaceutical composition that contains them
The present invention relates to branched alkylamino derivatives, their preparation method of thiazole and contain their pharmaceutical composition.
It is known that several thiazolamine derivatives are arranged.Patent application EP-0,462,264 have narrated wherein, and 2-position quaternary ammonium compound contains two substituent thiazolamine derivatives at least, and each substituting group has a heteroatoms at least, these substituting groups are the derivative of fragrance or aliphatic amine, perhaps also can be the derivative of acid, ketone, acid amides or thiophene ketone.All these compounds all are the PAF-acether antagonist and find that they are applied to treatment asthma, specific allergy or inflammatory status, cardiovascular disorder, hypertension and various ephrosis reason situation.Perhaps optionally as contraceptive, GB-2,022,285 has narrated and has had the compound that the adjusting relevant with immune response is active and have the anti-inflammatory performance.These compounds are the thiazole derivative that is replaced by secondary amine group in the 2-position.
The Hete rocyclic derivatives of some 2-(amido) thiazole is at patent application EP-0, narration arranged in 432,040.These compounds are the antagonist of cholecystokinin and gastrin.It also is known (patent application JP-0175475) that 2-amino-4,5-phenylbenzene thiazole derivative have the anti-inflammatory performance.2-amino-4-(4-hydroxy phenyl) thiazole derivative is as preparation 2, and the intermediate of 2-biarylchromeno-thiazole derivative also is known (patent application EP-0,205,069).Thiazole derivative is also at J.Chem.Soc. Perkin for 2-(N-methyl-N-benzylamino), and Trans 1, and (1984), 2, pp.147-153 reaches at J.Chem.Soc.Perkin Trans 1, (1983), and 2, narration is arranged among the pp.341-347.
In other thiazole derivative, EP-0,283,390 narrate and have required 2-[N-alkyl-N-(pyridyl alkyl) amino of following general formula] thiazole derivative:
Amine on these positions 2 is had excellent pharmacological properties and has especially with the maincenter choline and can be transported (transmission) relevant stimulating activity by the derivative that pyridyl (non-branched-chain alkyl) group replaces.Therefore they are useful as muscarinic receptor gaonist and find that they can be applicable to treatment memory imbalance and senile dementia.
It is about their new texture and their new pharmacology performance that The compounds of this invention is different from outside described herein other the thiazolamine derivative.
These compounds are thiazolamine derivatives, wherein have the substituent quaternary ammonium compound of alkyl or aryl (branched-chain alkyl) on 2 amine.
This specific structure gives product of the present invention excellent especially pharmacological properties.In fact, The compounds of this invention is in very low concentration-replace when being lower than 10 μ m 125Specific receptors bind on I-CRF and the mouse cortex film.Therefore The compounds of this invention becomes the setter of the active neuropeptide effect of corticotropin releasing factor(CRF) (CRF), control hypothalmus-pituitary-adrenal axis (hypothalamohyposioadrenal axis), and find that they are used for the treatment of and the stress reaction diseases associated, more generally be used for the treatment of with CRF pathological condition diseases associated as, psychosis for example, anxiety disorder, anorexia nervosa etc.
Theme of the present invention more particularly, is the branched alkylamino derivatives of general formula I thiazole, their steric isomer and and mineral acid or organic acid additive salt
Figure C9310943800111
Wherein-R 1Expression A 1Group or formula A 2Group; (its Chinese style X, Y and Z can be identical or different, represent hydrogen atom, halogen atom separately, contain the alkoxy grp of 1-5 carbon atom, the alkyl that contains 1-5 carbon atom, oh group, cyano group, nitryl group, trifluoromethyl group or contain the aromatic alkyl group of 7-9 carbon atom) ,-R 2Expression hydrogen atom, halogen atom, the alkyl group that contains 1-5 carbon atom, methylol groups or formyl radical group ,-R 3Expression contains the alkyl group of 1-5 carbon atom, the group of naphthene base that contains 3-8 carbon atom, the kiki alkenyl group that contains 2-6 carbon atom, the group of naphthene base that contains 4-8 carbon atom or phenyl group ,-R 4The expression hydrogen atom, contain 1-5 carbon atom alkyl group, contain the group of naphthene base of 3-6 carbon atom or contain the cycloalkylalkyl group of 4-8 carbon atom straight chain or side chain ,-R 5Expression contain the alkyl group of 1-5 carbon atom, arbitrarily by the group of naphthene base of 3-8 carbon atom of the alkyl group replacement that contains 1-5 carbon atom, contain 4-8 carbon atom straight chain or side chain the cycloalkylalkyl group, contain the alkenyl of 2-6 carbon atom or the group of Formula B (its Chinese style P equals 0,1,2 or 3 ,-R 6Expression phenyl group, pyridine group, imidazole group, pyrrole group, thienyl group or furan group (group wherein can be replaced by the group of one or more halogen atoms, the alkoxy grp that contains 1-5 carbon atom, the alkyl group that contains 1-5 carbon atom, oh group, cyano group, nitryl group, trifluoromethyl group, methylthio group group or formula B arbitrarily), perhaps expression contains 3-8 carbon atom arbitrarily by the group of naphthene base that alkyl group replaced that contains 1-5 carbon atom.-m and n can be identical or different, represent 0 or 1 separately.
Preferred compound of formula I of the present invention, their steric isomer and they and mineral acid or organic acid additive salt are: wherein-R 1Expression A 1Group ,-R 2Expression halogen atom or contain the alkyl group of 1-5 carbon atom ,-R 3Expression contain 1-5 carbon atom alkyl group, contain the group of naphthene base of 3-8 carbon atom or contain the kiki alkenyl group of 2-6 carbon atom ,-R 5Expression contain 1-5 carbon atom alkyl group, contain 3-8 carbon atom can be contained arbitrarily 1-5 carbon atom alkyl replacement group of naphthene base or contain the cycloalkylalkyl of 4-8 carbon atom straight chain or side chain, and-R 4, R 6, m and n be identical with the general formula I definition.
In these compounds, particularly preferred one group is by general formula I AThe compound, their steric isomer of expression and they and mineral acid or organic acid additive salt, Wherein :-Y and Z are identical with the general formula I definition ,-R 5The alkyl group of 1-5 carbon atom of expression or contain 3-8 carbon atom arbitrarily by the group of naphthene base of the alkyl group replacement that contains 1-5 carbon atom or contain the cycloalkylalkyl group of 4-8 carbon atom straight chain or side chain ,-R 6Expression phenyl group or pyridine group, (group wherein can be replaced by one or more halogen atoms, the alkoxy grp that contains 1-5 carbon atom, the alkyl group that contains 1-5 carbon atom, oh group, cyano group, nitryl group, trifluoromethyl group or methylthio group group arbitrarily), arbitrarily by containing the imidazole group that 1-5 carbon atom alkyl group replaces, perhaps contain 3-8 carbon atom and can be contained the group of naphthene base that 1-5 carbon atom group replaces arbitrarily
General formula I A-C 3H 7Group is represented the n-propyl group.
The term alkyl group or the kiki alkenyl group meaning refer to the straight or branched group.
Following compounds belongs to preferred compound of the present invention:
4-(4-chloro-2-methoxyphenyl)-5-methyl-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } thiazole,
4-(4-chloro-2-aminomethyl phenyl)-5-methyl-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } thiazole,
4-(2-chloro-4-aminomethyl phenyl)-5-methyl-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } thiazole,
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } thiazole,
5-bromo-4-(2,4 dichloro benzene base)-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-(2-propenyl)-N-[1-(4-pyridyl) ethyl] amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-(α-Jia Jibianji)-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopropyl (4-pyridyl) methyl]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[1-(2-methyl-4-pyridyl) ethyl]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{ N-[1-(4-imidazolyl) ethyl]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-propyl group-N-[1-(4-pyridyl) propyl group] amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[2-methyl isophthalic acid-(4-pyridyl) propyl group]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl)-N-third amino] thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl-4-methoxybenzyl)-N-third amino] thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopropyl (2-thienyl) methyl]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(bicyclic methyl propyl)-N-third amino] thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopentyl benzyl)-N-third amino] thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{ N-[cyclopentyl (4-pyridyl) methyl]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl-4-luorobenzyl)-N-third amino] thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[(3-chloro-4-pyridyl) (cyclopropyl) methyl]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-propyl group-N-[α-(4-pyridyl) benzyl] amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopropyl (4-imidazolyl) methyl]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[α-cyclopropyl-3-(trifluoromethyl benzyl]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopentyl (cyclopropyl) methyl]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopropyl (1-methyl-4-imidazolyl) methyl]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{ N-[cyclopropyl (1-benzyl-4-imidazolyl) methyl]-N-third amino } thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopropyl (2-pyridyl) methyl]-N-third amino } thiazole,
4-(2-chloro-4-aminomethyl phenyl)-5-methyl-2-[N-(bicyclic methyl propyl)-N-third amino] thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopropyl (3-pyridyl) methyl]-N-third amino } thiazole,
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(bicyclic methyl propyl)-N-third amino] thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclobutyl benzyl)-N-third amino] thiazole,
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(2,2-two cyclopropyl ethyls)-N-third amino] thiazole.
All these compounds all can be the form of free alkali or the form of salt.
Theme of the present invention is the preparation method of compound of Formula I also, it is characterized in that alpha-halogen, be preferably alpha-brominated, formula II carbonyl derivative
Figure C9310943800171
R wherein 1Definition identical with general formula I, R 2' expression hydrogen atom or contain the alkyl group of 1-5 carbon atom and Hal represents halogen atom, perhaps the thiocarbamide with formula III reacts
Figure C9310943800172
R wherein 3, R 4, R 5Identical with n with definition in the general formula I, and R 6' with R 6Define identical, except when R 6When containing the functional group for active N atom, at this moment corresponding to R 5R 6The wherein said active group H of ' expression group atom can the protecting group of anti-hydrolysis be replaced in alkaline medium.
To form general formula I ' compound:
Figure C9310943800181
Wherein-R 1, R 3, R 4, R 5, m and n be identical with definition in the general formula I ,-R 2' identical with definition among the general formula I I, and-R 6' identical with definition in the general formula III, perhaps with formula III AThiocarbamide reaction
Figure C9310943800182
R wherein 4, R 5, m and n definition and general formula I in identical, and R 6' identical with the general formula III definition, to form general formula I V compound: R wherein 1, R 4, R 5, m and n be identical with the definition of general formula I, R 2' identical with general formula I I definition, and R 6' identical with the general formula III definition,
Halide reaction with formula V
Hal-R 3(V) wherein Hal represents halogen atom, and R 3It is identical with the general formula I definition,
To form general formula I ' compound, R then-wherein 2Formula I ' the compound of ' expression hydrogen atom
* or with halogen react, form R 2The compound of Formula I of expression halogen atom, then,
Work as R 2During the expression bromine atoms, can form R with another halogen reaction 2Represent this halogen
Plain compound of Formula I.
* or with oxalyl chloride react, to prepare wherein R 2General formula I chemical combination for the formyl group
Thing, it can obtain wherein R through reduction reaction again 2General formula Iization for methylol
Compound, perhaps-general formula I ' compound, wherein R 6' expression and active N atom have the radicals R of protecting group 6, make it to carry out acid hydrolysis, obtain wherein R 6The compound of Formula I that contains primary amine or secondary amine group, and, if be fit to compound of Formula I
Can then be separated into their possible steric isomers and/or form corresponding salt with mineral acid or organic acid salinization.
General formula I V compound as preparation compound of Formula I intermediate also constitutes a part of the present invention.
The derivative of general formula I I can be by corresponding formula R 1-CO-CH 2-R 2' not halogenation ketone obtain, perhaps in appropriate organic solvent such as acetate, tetracol phenixin or ether, act on by bromine, or according in Bull.Chem.Soc.Japan (1987), 60, method described in pp.1159-1160 and the pp.2667-2668, by the effect of level Four ammonium tribromide, perhaps also can in the mixture of organic solvent such as chloroform and ethyl acetate, act on by bromize alpha ketone (J.Org.Chem. (1964), 29, pp.3451-3461).
Formula R 1-CO-CH 2-R 2' ketone, generally speaking, be known and commercial available product.These compounds can be in the presence of Lewi ' s acid, by the Friedel-Cvafts reaction, by formula R 1The compound of H and formula R 2' CH 2COHal acetyl halide compound prepared in reaction is preferably used formula R 2' CH 2The acyl chlorides of COCl.
R wherein 1For at 2 and 4 formula A that replaced by halogen atom 2Group, and R 2' be the general formula I I compound of methyl, can pass through the halogeno-benzene derivative, particularly adopt 1, the 3-phenyl-dihalide in the presence of aluminum chloride, obtains with the 2 bromo propionyl bromide reaction.
General formula I I and III ACompound can pass through general formula VI compound
Figure C9310943800211
R wherein 3' identical with definition in the general formula I or represent hydrogen atom, R 6' with general formula III in the identical and W of definition represent phenyl group or tertiary butyl groups, perhaps obtain being preferably hydrochloric acid with acid treatment, perhaps obtain being preferably sodium hydroxide with alkaline purification.
When W is phenyl group, work as R especially 6Can adopt mineral acid treatment during ' expression pyridine group.Work as R 5During for cycloalkyl such as cyclopropyl and work as R 6For on the N atom by alkaline medium be the protecting group of anti-hydrolysis replace imidazolyl the time, adopt the A alkaline purification.
When W represents tertiary butyl groups, formula III and III AThiourea derivative can by general formula VI compound by strong acid such as concentrated hydrochloric acid effect, under 10 ℃ of-100 ℃ of temperature, obtain.
Formula VI compound can obtain by the amine reaction of isothiocyanic acid benzyl acyl ester (benzoyl isothiocyanate) or isothiocyanic acid valeryl ester (pivaloyl isothiocyanate) and general formula VII:
Figure C9310943800212
R wherein 4, R 5, m and n be identical with definition in the general formula I, R 3' define identical and R with general formula VI 6' identical with the general formula III definition.
The amine of general formula VII, secondary amine is relevant here, can prepare by standard method.
According to first method, corresponding formula VII AThe alkyl of primary amine
Figure C9310943800221
Changing, is the alkyl halide Hal-R with formula V 3Reaction is carried out, preferably at heated condition, an alkali metal salt in polar organic solvent, dimethyl formamide for example, existence under carry out.
According to another alkylating method, the amine that is formula VIIA in the organic solvent that is selected from halohydrocarbon such as methylene dichloride, by carboxylic acid halides or acid anhydrides effect, proton acceptor be preferably triethylamine in the presence of carry out.React the acid amides of gained thus and in ether type organic solvent, use hydride (AlLiH 4Or analogue) reduction.
Two above-mentioned methods particularly preferably are the pure isomeric forms that is used to prepare general formula VII compound.
Another method of preparation general formula VII compound is included in the dehydration medium and makes formula R 3NH 2Primary amine and ketone condensation obtain corresponding imines, adopt metal hydride then, be preferably sodium borohydride, reduce in the mode of routine, perhaps in the presence of suitable catalyst, use hydrogen reducing.At formula R 3NH 2Primary amine and ketone in the reaction of dehydration medium, preferred or adopt titanium tetrachloride (IV) (TiCl 4) or adopt Catalyzed by p-Toluenesulfonic Acid.
M and n are the amine of the formula VII of O, preferably carry out according to the method for following route principle.Steps A
Figure C9310943800231
Step B
Figure C9310943800232
The condensation reaction of primary amine and aldehyde is preferably at room temperature carried out in ethanol or toluene in the steps A.The reaction of imines and lithium alkylide derivative is to carry out under 0 ℃ of-15 ℃ of temperature in ether or tetrahydrofuran (THF) in step B.
Mentioned as the front, worked as substituent R 6When having active function group, these functional groups must be protected in a usual manner.For example, work as R 6During the expression imidazole group, its active group (NH) can be by trityl as protecting group, behind the generation general formula I derivative, adopts the mineral acid example hydrochloric acid to remove protecting group.If desired, also can prepare the derivative that on imidazole group, replaces.At last, R 6For the compound of Formula I of imidazole group and as alkyl halide or aralkyl halide reaction.This is reflected under the existence of an alkali metal salt and carries out in polar solvent such as dimethyl formamide, preferably carries out under heated condition.Can obtain N-alkyl or N-aralkyl imdazole derivatives like this.
The alkylation of general formula I V compound is to carry out in the presence of alkali (sodium hydride, cesium carbonate, salt of wormwood etc.).When this reaction is when carrying out in the presence of alkaline carbonate, adopt polar solvent as solvent, for example dimethyl formamide.When alkylation is when carrying out in the presence of hydride, preferably use tetrahydrofuran (THF), also may use aromatic hydrocarbon.When reaction is when carrying out in the presence of hydrogen base lithium, preferably adopt tetrahydrofuran (THF) as solvent.Formula II compound and formula III or formula III AThe reaction of thiocarbamide is to carry out in the presence of organic bases such as triethylamine in organic medium.
Go up 5 of unsubstituted compound of Formula I preparations by 5 and go up the general formula I thiazole derivative that is replaced by halogen atom, this reaction at room temperature adopts alkyl halide to carry out as solvent.Preferably in the presence of proton acceptor, carry out.
5 compound of Formula I that replaced by halogen atom can be prepared by their analogue-5 compound of Formula I that is replaced by bromine atoms.Latter's compound after halogen/metal exchange by the halogenating agent effect.
5 formula I thiazole derivatives that replace by the formyl group, by obtaining after corresponding 5 unsubstituted derivatives and the oxalyl chloride reaction.React preferably in organic solvent such as the dimethyl formamide and carry out.5 general formula I thiazole derivatives that replaced by the formyl group obtain 5 compound of Formula I that replaced by methylol group of thiazole heterocycle by reductive agent such as sodium borohydride effect.Reaction is to carry out under about 0 ℃ of-35 ℃ of temperature at alcoholic solvent.
R wherein 1The formula A that expression is replaced by at least one oh group 1Or A 2The compound of Formula I of group can be by R wherein 1The formula A that expression is replaced by one or more methoxy groups 1Or formula A 2The compound of Formula I preparation of group.At last, latter's product is by acid effect, for example Hydrogen bromide.In this case, reaction is to carry out at heated condition.
The salt of compound of Formula I and pharmaceutically acceptable acid or alkali is preferred salt.But those make compound of Formula I to separate, and particularly purifying or obtain the salt of pure isomer also is a purpose of the present invention.
Prepare in the pharmaceutically acceptable acid of acid salt with compound of Formula I, can mention hydrochloric acid, phosphoric acid, fumaric acid, citric acid, oxalic acid, sulfuric acid, xitix, tartrate, toxilic acid, amygdalic acid, methylsulfonic acid, lactobionic acid, glyconic acid, saccharic acid, hydroxyethyl methylsulfonic acid, succinyl-sulfonic acid etc.
The compounds of this invention has extremely excellent pharmacological properties.The compounds of this invention, when being lower than 10 μ m concentration (0.01-10 μ m) replaces on mouse cortex especially 125I-CRF combines with special receptor, and this is according to De.Souza E.B. (J.Neurosci (1987), 7 (1), pp.88-100) described method.This is amazing and unexpected, because the compound close with structure of the present invention, but wherein the amine of 2 of thiazole rings does not contain the substitution in side chain base, can not obviously replace 125The combination of I-CRF.
In fact, patent application EP-0, compound 2-[N-methyl-N-(3-pyridylmethyl) amino described in 283,390 embodiment 112]-4-(2,4, the 6-trimethylphenyl) thiazole, in concentration -3During M. only produce about 8% replacement.
Corticotropin releasing factor(CRF) (CRF) is the active neuropeptide of a kind of control hypothalmus-pituitary-adrenal axis.This factor is that stress reaction relevant internal secretion and behavior reaction are responsible for.
In fact, proved that CRF can regulate behavior, and autonomic certain function (G.F.Koob, F.E.Bloom, Fed.Proc. (1985), 44, p.259; M.R.Brows, L.A.Fisher, Fed.Proc. (1985), 44, p.243).More specifically, CRF induce thyroliberin (ACTH), beta-endorphin and by other secretion from former other peptide of opium casting skin matter hormone derivative (A.Tazi etc., Regul.Peptides (1987) 18, p.37; M.R.Brown etc., Regul.Peptides (1986) 16, p.321; C.L.Williams etc., Am.J.physiol. (1987), G582, p253).
Therefore The compounds of this invention can be used for regulating the secretion of endogenous material.Find that more specifically they can be applicable to weaken stress reaction (behavior, emotional state, stomach and intestine and cardiovascular disorder, immune system disorder), and more through being usually used in the various pathological states relevant, for example psychosis, anxiety disorder, anorexia nervosa etc. with CRF.
The present invention also extends to pharmaceutical composition, contains at least a formula I compound as activeconstituents, or a kind of salt of forming of it and pharmaceutically compatible mineral acid or organic acid, with one or more inertia suitable carriers be combined intos.
The pharmaceutical composition that obtains like this can make easily various forms as, for example tablet, dragees, hard gelatin capsule, suppository, and be used to inject or oral solution.
Dosage alters a great deal according to the character of age of patient and body weight, disease and severity and route of administration.Generally speaking, the single dose scope is at 0.5-200mg, and treatment dosage every day that is used for the people is between 0.5-mg-800mg.
Preferred route of administration is oral or parenterai administration.
The following examples do not limit, and the present invention has been described.
Fusing point adopts the Micro-Kofler technical measurement.
Suitable, write down at 200MHz-100MHz or 80MHz place compound of Formula I proton magnetic resonance (PMR) ( 1H NMR) spectrum.
The percentage analysis of The compounds of this invention is consistent with theoretical value.
Preparation
The preparation preparation 1 of general formula I I compound
2-bromo-1-(2,4, the 6-trimethylphenyl)-1-ethyl ketone
(compound 1)
1-(2,4, the 6-trimethylphenyl)-1-ethyl ketone of 0.3mol is dissolved in the 200ml glacial acetic acid, keeps the reaction medium temperature to be lower than 10 ℃ and drip the 31.8g bromine.After having added, make reaction medium get back to room temperature and kept 2 hours in this temperature.Then with in the reactant impouring 500ml icy water and use extracted with diethyl ether.Earlier use salt water washing organic layer again, use anhydrous magnesium sulfate drying with saturated sodium bicarbonate aqueous solution.
Boil off solvent, the oil of gained can use without just being further purified.
Other compound (compound 2-13)
According to preparation 2-bromo-1-(2,4, the 6-trimethylphenyl)-described method of 1-ethyl ketone, adopt suitable ketone to obtain in the following compound as initiator.Compound 2:2-bromo-1-(2-naphthyl)-1-acetonide 3:2-bromo-1-(2, the 4-3,5-dimethylphenyl)-1-acetonide 4:2-bromo-1-(4-chloro-2-aminomethyl phenyl)-1-acetonide 5:2-bromo-1-(2-chloro-4-aminomethyl phenyl)-1-acetonide 6:2-bromo-1-(2-chloro-4-p-methoxy-phenyl)-1-acetonide 7:2-bromo-1-(2, the 4-Dimethoxyphenyl)-1-acetonide: 2-bromo-1-(4-chloro-phenyl-)-1-acetonide 9:2-bromo-1-(1-naphthyl)-1-acetonide 10:2-bromo-1-(2,4 dichloro benzene base)-1-ethyl ketone compound 11:2-bromo-1-(4-p-methoxy-phenyl)-1-acetonide 12:2-bromo-1-(4-chloro-2-p-methoxy-phenyl)-1-acetonide 13:2-bromo-1-(4-aminomethyl phenyl)-1-acetone prepares II
2-bromo-1-(2,4, the 6-trimethoxyphenyl)-1-acetone
(compound 14)
Make under this temperature, to add 25.1g 1-(2,4, the 6-the trimethoxyphenyl)-1-acetone that is dissolved in the 150ml chloroform fast by the suspension returning of 45.3g cuprous bromide in the 150ml ethyl acetate, a large amount of yellow-green precipitates occurs.
Reactant was refluxed 2 hours 30 minutes, make it to drop to room temperature then, the filtering insoluble salt washs with ethyl acetate.
Organic phase is handled with bone black, and after the solids removed by filtration, concentrating under reduced pressure is to obtain oil.(6: mixture 4/V/V) adopts chromatography purification as elutriant on silicagel column to adopt hexanaphthene and acetate ethyl ketone.Oil productive rate: 60% preparation III
2-bromo-1-(2,4 dichloro benzene base)-1-acetone
(compound 15)
At room temperature, 17.4g tertiary butyl tribromide ammonium is added in the 420ml methylene dichloride and 140ml methanol mixture that has dissolved 7g 1-(2,4 dichloro benzene base)-1-acetone.
After 24 hours, the vacuum-evaporation reactant is to doing.
With water dissolution, ethyl acetate extraction, the organic phase dried over sodium sulfate.
Evaporate under the vacuum, the mixture that adopts hexanaphthene and ethyl acetate (20: 1 V/V) then is as eluent, purifying on silicagel column.Oil productive rate: 78%.
2-bromo-1-(2-chloro-4-p-methoxy-phenyl)-1-acetone (compound 6) also can obtain in the same way.Preparation IV
2-bromo-1-(2, the 4-dibromo phenyl)-1-acetone (compound 16)
At 0 ℃ 15g aluminum chloride carefully is added to 25g 1, in the 250ml dithiocarbonic anhydride of 3-dibromobenzene, and slowly adds in the 2 bromo propionyl bromide of 22.86g.
Refluxed 8 hours, vacuum steams dithiocarbonic anhydride, and reaction medium is poured on the trash ice.
Extract secondary with heptane, be evaporated to driedly, purifying on silicagel column is made eluent with hexanaphthene and ethyl acetate (10: 1 V/V) mixture, desired product.Yield: 76%.
Above described method, can be used to prepare 2-bromo-1-(2,4 dichloro benzene base)-1-acetone (compound 15) and 2-bromo-1-(3, the 5-dichlorophenyl)-1-acetone (compound 17).
Use the same method, replace 1 with 1-chloro-3-iodobenzene, the 3-dibromobenzene is made starting raw material can prepare 2-bromo-1-(2-chloro-4-iodophenyl)-1-acetone (compound 18).
The preparation of formula VII compound prepares V
N-(2-cyclopropyl benzyl) propylamine (compound 19)
In the 60ml dry toluene of 10g cyclopropyl phenyl ketone, add the 4_ molecular sieve, 100mg is to a toluenesulphonic acids and 6g propylamine.
With the generation of gas-chromatography discriminating amine, 55 ℃ of heating are after 6 days, and reaction mixture filters molecular sieve, and vacuum-evaporation is to doing.
Resistates is dissolved in the 100ml dehydrated alcohol, is chilled to 0 ℃, with the adding 2.65g sodium borohydride of small portion amount, stirred overnight at room temperature, vacuum-evaporation is to doing, and is water-soluble, with N hydrochloric acid water medium to pH be 2, wash with ethyl acetate, add 2N sodium hydroxide and make pH9, then several times with dichloromethane extraction.
Organic phase after the dry also evaporation is an oily matter, can directly use.Yield: 60% proton NMR spectrum (solvent C DCl 3) 0.15-1.7ppm, m, 11H; 2.4ppm, t+d, 2H; 2.80ppm, d, 1H; 7.3-7.4ppm, m, 5H;
Other compound (compound 20 to 47)
According to method recited above, can obtain the amine shown in the table 1
Table I
Figure C9310943800311
Table I (continuing)
Figure C9310943800331
Preparation VI
N-[cyclopropyl (4-pyridyl) methyl] propylamine (compound 20)
Also can prepare N-[cyclopropyl (4-pyridyl) methyl with following method] the propylamine steps A
1.07g 4-pyridine aldehydes is dissolved in the 10ml dehydrated alcohol, and slowly add 0.8g just-propylamine
Stir after 30 minutes, be evaporated to dried 1.48g oily matter yield: 99% step B
The amine of preceding step gained is dissolved in the anhydrous isopropyl ether of 10ml.
Under 0 ℃ of stirring, this solution is added in the isopropyl ether solution of 30ml cyclopropyl lithium (20mmol).After the stirring at room 2 hours, be chilled to 0 ℃, drip 3ml methyl alcohol, add 10ml 30% anhydrous chlorides of rase ammonium solution again.
Extraction ether phase with N hydrochloric acid
With in the sodium bicarbonate and acidic aqueous solution, use ethyl acetate extraction.
Dry on anhydrous sodium sulphate, be evaporated to dried colorless oil.Yield 80% proton NMR spectrum (CDCl 3Solvent) 0.28ppm, m, 8H; 0.88ppm, t, 3H; 1.48ppm, m, 2H; 2.31-2.49ppm, m, 2H; 2.78ppm, d, 1H; 7.35ppm, dd, 2H; 8.54ppm, dd, 2H.
Other compound (compound 48 to 60)
According to method recited above, obtain the amine shown in the Table II.
Table II
Figure C9310943800352
Preparation VII
N-(cyclopropyl methyl)-1-(4-pyridyl) ethamine (compound 61) steps A
In the 250ml three-necked flask under argon gas, the 3.2ml cyclopropane-carboxylic acid is dissolved in the 20ml anhydrous methylene chloride, on ice bath, cools off, add the 8.4g dicyclohexyl carbodiimide that is dissolved in the 20ml anhydrous methylene chloride, stirred 30 minutes, and added 5g 1-(4-pyridyl) ethamine.Stirred overnight at room temperature is filtered, and discards white crystal, evaporated filtrate, and purifying gained residue on silica gel is made eluent with ethyl acetate and hexane (1: 9 V/V) mixture, gets white powder.Yield: 95% step B
In the 250ml three-necked flask of band titration conduit and prolong, steps A gained 6g acid amides is dissolved in the 20ml anhydrous tetrahydro furan.Reflux, the tetrahydrofuran solution (20ml) of adding 63ml borane-methyl-sulfide mixture.Reflux 3 hours, cooling, and drip 20ml 3N hydrochloric acid soln.Reflux 1 hour with the caustic soda alkalization, is used ethyl acetate extraction, and is dry on anhydrous sodium sulphate, is evaporated to dried.Yield: 88% proton NMR spectrum (solvent C DCl 3): 0.02-0.07ppm, m, 2H; 0.37-0.50ppm, m, 2H; 0.8 7-0.94ppm, m, 1H; 1.33ppm, d, 3H; 2.29ppm, dd, 2H; 3.77ppm, q, 1H; 7.22-7.25ppm, dd, 2H; 8.53ppm, d, 2H.Preparation VIII
N-propyl group-α-xylylamine (compound 62)
The 23ml propylamine is imported in the 200ml dimethyl formamide, add 32g cesium carbonate and 9.25g α-Jia Bianji bromine, room temperature left standstill 4 hours, was evaporated to driedly, water-soluble, use ethyl acetate extraction, and drying on anhydrous sodium sulphate is evaporated to dried the product of desiring.Yield: 95% proton NMR spectrum (solvent C DCl 3);
2.19-2.54ppm, m, 2H; 3.75ppm, g, 1H; 0.86ppm, t, 3H; 1.34ppm, d, 3H; 1.17-1.64ppm, m, 2H; 7.19-7.29ppm, m, 5H. prepares IX
N-[cyclopropyl (3-pyridyl) methyl] propylamine (compound 63) steps A
45ml 0.625M cyclopropyl lithium is added drop-wise in the anhydrous diethyl ether, under-78 ℃ of stirrings, is added in the 70ml anhydrous diethyl ether of 3g 3-pyridine aldehydes, rise to room temperature, add the saturated aqueous solution of ammonium chloride, use ethyl acetate extraction, use dichloromethane extraction again.Yield: 78% step B
Preceding step gained 3.35g cyclopropyl (3-pyridyl) carbinol compound is dissolved in the 75ml diox, and adds 13.66g Manganse Dioxide, reflux and stir after 4 hours, while hot by the diatomite filtration reaction medium.Put forward organic solution after the vacuum-evaporation, residue is chromatogram purification on silicagel column, makes eluent with hexanaphthene and ethyl acetate mixture (1: 1 V/V), gets cyclopropyl 3-pyridone yield: 80% proton NMR spectrum (solvent C DCl 3):
1.06-1.34ppm, m, 4H; 2.68, m, 1H; 7.42ppm, m, 1H; 8.23ppm, m, 1H; 8.78 ppm, m, 1H; 9.26ppm, m, 1H. step C
With preparation V described method, with the ketone of preceding step gained, N-[cyclopropyl (3-pyridyl) methyl] propylamine prepares X
N-[cyclopropyl (2-methyl-4-pyridyl) methyl] propylamine (compound 64) steps A
In the anhydrous four ammonia furans of the 100ml that-65 ℃ of tetrahydrofuran solutions with 130ml 0.7M cyclopropyl lithium are added to 7.3g 4-cyano group-2-picoline, stir after 4 hours, add methyl alcohol and ammoniumsulphate soln (6.3g is in 20ml water), after ether extraction, wash organic phase with water, vacuum-drying and evaporation, residue is purifying on silicagel column, and (98: 2V/V) mixture is made eluent with methylene dichloride and methyl alcohol.
Get cyclopropyl 2-methyl-4-pyridone yield thus: 59% proton NMR spectrum (solvent C DCl 3):
0.94-1.38ppm，m，4H；，2.62ppm，s，3H；2.52-2.65
Ppm, m, 1H; 7.57ppm, m, 2H; 8.65ppm, d, 1H. step B
According to the described method of preparation V,, get N-[cyclopropyl (2-methyl-4-pyridyl) methyl with the ketone of preceding step gained] propylamine.Preparation XI
N-(1,2-two cyclopropyl ethyls) propylamine (compound 65)
The 6.9ml propylamine is added to 2.2g encircles in the 85ml methylene dichloride of the third methyl cyclopropanone, drip the dichloromethane solution of 7ml 1M titanium chloride (IV) in room temperature, stirs after 18 hours, adding 40ml anhydrous methanol is chilled to 0 ℃ and adds the 1.0g sodium borohydride with a small amount of form.After the stirred overnight at room temperature, add 10ml water and vacuum-evaporation, water-soluble, use dichloromethane extraction, use the 2N hydrochloric acid extraction.Wash with ether, use in the strong caustic and water, use dichloromethane extraction, dry on anhydrous sodium sulphate, be evaporated to the dried colorless oil of putting forward.Yield: 76% proton NMR spectrum (solvent C DCl 3): 0.0-0.9ppm, m, 13H; 1.2-1.75ppm, m, 5H; 2.3-2.7ppm, m, 2H.
Other compound (compound 66 to 70)
According to the described method of preparation XI, get the amine that Table III is represented, prepare compound 70 from the cyclopropyl methyl phenyl ketone, the cyclopropyl methyl phenyl ketone is to make from cyclopropyl acetonitrile and phenyl-magnesium-bromide.
Table III
Figure C9310943800412
Preparation XII
N-(2,2-two cyclopropyl ethyls) propylamine (compound 71)
According to the described method of preparation V, from 2,2-two cyclopropyl acetaldehyde prepare this title compound.Preparation XIII
N-(1-phenyl-4-pentenyl) propylamine (compound 72) steps A
-70 ℃ under argon gas, will be dissolved in the 20ml ether 0.48ml and encircle third monobromomethane and stir, add 3ml tert-butyl lithium (1.7M pentane) solution again.
Stir 30 minutes step B
With the described method of preparation VI steps A, replace the 4-pyridine aldehydes with phenyl aldehyde.Step C
Be dissolved in the 730mg imines of gained in step C in the 2ml ether, slowly be added in the reaction soln of steps A gained.
Temperature is risen to 0 ℃ gradually, drip ammonium chloride solution then.
Isolate the ether phase from aqueous phase, use the ether extraction water, merge the ether phase, with 50ml1N hydrochloric acid extraction secondary.
With 1N sodium hydroxide solution alkalization water, use 50ml dichloromethane extraction 3 times.
Organic extracting solution that the washing of water and saturated aqueous sodium chloride merges, dry on anhydrous sodium sulphate, be evaporated to dried oily matter.Yield: 81% proton NMR spectrum (solvent C DCl 3): 0.77-0.92ppm, m, 3H; 1.27-1.93ppm, m, 6H; 2.23-2.45ppm, m, 2H; 3.57ppm, t, 1H; 4.87-5.03ppm, m, 2H; 5.60-5.82ppm, m, 1H; 7.25-7.41ppm, m, 5H. prepares XIV
N-(α-tert-butyl benzyl) propylamine (compound 73)
The 20ml ether is added in the 3ml tert-butyl lithium solution (1M pentane), stirred about 30 minutes, add the 730mg imines of the described preparation of preparation XIII step B that is dissolved in the 2ml ether at-70 ℃.
Improve temperature to 0 ℃ gradually, be hydrolyzed with aqueous ammonium chloride solution then.
Separate the ether phase, use the ether extraction water, merge the ether phase, use the 100ml hydrochloric acid extraction.
With the sodium hydroxide solution acid water that alkalizes, use dichloromethane extraction then.
Organic phase washes with water earlier, then washes with saturated aqueous sodium chloride, and is dry on anhydrous sodium sulphate, is evaporated to dried oily matter.Yield: 88% proton NMR spectrum (solvent C DCl 3): 0.84-1.0ppm, m, 12H; 1.36-1.55ppm, m, 2H; 2.29-2.46ppm, m, 2H; 3.30ppm, s, 1H; 7.19-7.35ppm, m, 5H.
The preparation of formula III compound prepares XV
N-[cyclopropyl (4-pyridyl) methyl]-N-propyl group thiocarbamide (compound
74) steps A
N 1-benzyl acyl group-N-[cyclopropyl (4-pyridyl) methyl]-N-propyl group thiocarbamide
The 0.88g ammonium thiocyanate is dissolved in the 6ml anhydrous propanone, is chilled to 0 ℃, slowly be incorporated in the 1.1ml Benzoyl chloride in the 1ml acetone, refluxed 10 minutes, add 2g N-[cyclopropyl (4-pyridyl) methyl that is dissolved in the 10ml acetone] propylamine (compound 20), heat after 1 hour, steam solvent.
Residuum is water-soluble, gets the white crystal compound of being desired.Yield: 75% fusing point: 171 ℃ of step B
18ml 1N sodium hydroxide is added in the 2.5g compound that is dissolved in the top step gained in the 50ml ethanol, reaction medium 80 ℃ 48 hours, add the sodium hydroxide of 10ml 1N again, kept 24 hours at 80 ℃ again.
After steaming ethanol under the vacuum, with the water of dichloromethane extraction gained.
Vacuum-drying organic phase and evaporation.
Use silica gel chromatography, with methylene dichloride and methyl alcohol (98: 2V/V) make eluent.Yield: 68% fusing point: oily.Proton NMR spectrum (solvent C DCl 3): 0.85ppm, t, 3H; 0.54-1.25ppm, m, 8H; 1.78ppm, m, 2H; 2.84-3.35ppm, m, 2H; 6.03ppm, d, 1H; 6.19ppm, s, 2H; 7.42ppm, d, 2H; 8.58ppm, dd, 2H.
Other compound (compound 75 to 113)
According to N-[cyclopropyl (4-pyridyl) methyl]-the described method of N-propyl group urea, with above-mentioned suitable amine (preparation of formula VII compound), or can obtain Table IV a and the represented thiourea derivative of IVb from the commercial amine that obtains
Table IV a
Figure C9310943800461
Figure C9310943800462
Figure C9310943800471
Table IV a (continuous 1)
Figure C9310943800481
Table IV a (continuous 2)
Table IV b Preparation XVI
N-[1-(3-chloro-4-pyridyl) ethyl]-(change of N-propyl group thiocarbamide
Compound 116) steps A
N '-benzoyl-N-[1-(3-chloro-4-pyridyl) ethyl]-N-propyl group-thiocarbamide
According to preparation XV steps A described method,, 1.74ml Benzoyl chloride and 2.7g N-[1-(3-chloro-4-pyridyl) ethyl from the 1.14g ammonium thiocyanate] propylamine (compound 22) makes this title compound.Step B
6ml 32% hydrochloric acid is added in the 1.18g compound of steps A gained, reaction medium in 80 ℃ 1 hour, cooling adds water, uses dichloromethane extraction, discards organic phase, with the yellow soda ash water that alkalizes, uses dichloromethane extraction.Vacuum-drying organic phase and evaporation.Use the silica gel chromatography purifying, make eluent with methylene dichloride and methyl alcohol (98: 2 V/V) mixture.Yield: 93% fusing point: oily matter proton NMR spectrum (solvent C DCl 3): 0.73ppm, t, 3H; 1.05-1.66ppm, m, 2H; 1.63ppm, d, 3H; 3.16ppm, t, 2H; 5.87ppm, s, 2H; 6.77ppm, g, 1H; 7.29ppm, d, 1H; 8.53ppm, d, 1H; 8.59ppm, s, 1H.
Other compound (compound 117 to 121)
According to preparation N-[1-(3-chloro-4-pyridyl) ethyl]-the described method of N-propyl group thiocarbamide, can obtain thiourea derivative represented in the Table V.
Table V
Figure C9310943800521
Preparation XVII
N-cyclopropyl methyl-N-[1-(4-pyridyl) ethyl] thiocarbamide (chemical combination
Thing 122) steps A
N '-valeryl-N-cyclopropyl methyl-N-[1-(4-pyridyl) ethyl]-thiocarbamide
Under argon gas, in the 100ml three-necked flask, the 2.9g potassium sulfocyanate is dissolved in the 30ml acetone, is chilled to 0 ℃, drip 3.The 4ml pivalyl chloride in 0 ℃ of stirring 5 hours, adds 4.8g N-(cyclopropyl methyl)-1-(4-pyridyl) ethamine (compound 61) then.Stirred overnight at room temperature is evaporated to driedly, and residue is water-soluble, uses dichloromethane extraction.Dry on anhydrous sodium sulphate, and be evaporated to dried.The gained meal is washed and is filtered with hexane.Yield: 75% proton NMR spectrum (solvent C DCl 3): 0.02-0.07ppm, m, 2H; 0.4-0.5ppm, m, 2H; 0.96ppm, m, 1H; 1.28ppm, s, 9H; 1.77ppm, d, 3H 2.90ppm, dd, 2H; 3.4ppm, m, 1H; 6.5ppm, s, 1H; 7.4ppm, m, 2H; 8.61ppm, d, 2H. step B
Top step gained 2g product is dissolved in 15ml 32% hydrochloric acid, be heated to 70 ℃ 1 hour, cooling with saturated aqueous solution of sodium bicarbonate alkalization, use ethyl acetate extraction, drying is evaporated to dried on anhydrous sodium sulphate.Residue is dissolved in hexane and ethyl acetate (8: the 2 V/V) mixture.
Isolated by filtration white crystal yield: 87%
Other compound (compound 123 to 129)
According to the described method of preparation XVII, can obtain the thiocarbamide shown in the Table VI.
Table VI
Figure C9310943800551
EXAMPLE Example 1
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl)-N-third amino] thiazole
In the 35ml ethanolic soln of 1.35g N-(α-cyclopropyl benzyl)-N-propyl group thiocarbamide (compound 75), add the 546mg triethylamine, slowly add 1.52g 2-bromo-1-(2,4 dichloro benzene base)-1-acetone (compound 15) then.Be heated to 75 ℃ after 3 hours, remove by filter formed precipitation, ethanolic soln is evaporated to dried, residue is dissolved in the ether, washes with water till bromide anion disappears.Dry organic phase on anhydrous sodium sulphate, and be evaporated to dried.Purifying residue on silicagel column is made eluent with hexanaphthene and ethyl acetate (10: 1 V/V) mixture, product is desired by institute, usefulness acetonitrile recrystallization (white crystal).Yield: 79% fusing point: 78 ℃ of-81 ℃ of proton NMR spectrums are illustrated in embodiment 2 in the Table VII
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopropyl (4-pyridyl) methyl]-N-third amino } thiazole
According to embodiment 1 described method, starting raw material is with 1.2g N-[cyclopropyl (4-pyridyl) methyl]-N-propyl group thiocarbamide (compound 74) and 1.52g 2-bromo-(2,4 dichloro benzene base)-1-acetone (compound 15) makes this title compound.This product purifying on silicagel column, (98: 2V/V) mixture is made eluent with methylene dichloride and methyl alcohol.Oil yield: 78%
From this alkali, be dissolved in the ethanol with suitable acid, obtain following salt :-hemifumarate: fusing point: 98 ℃-hydrochloride: fusing point: 68 ℃-pyrosulphate: fusing point: 186 ℃
The proton NMR spectrum of this product is illustrated in the Table VII.Embodiment 3 to 40
According to embodiment 1 described method, can obtain embodiment 3-40 compound with suitable bromoketone and thiourea derivative, spectral quality is illustrated in the Table VII.Embodiment 41
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(Alpha-Methyl-benzyl)-N-(cyclopropyl methyl) amino] thiazole
At 0 ℃, the 0.5g 4-(2 that is dissolved in the 5ml anhydrous tetrahydro furan, the 4-dichlorophenyl)-and 5-methyl-2-[N-(α-Jia Bianji) amino] thiazole (making from compound 92 and compound 15) and 66mg sodium hydride according to embodiment 1 described method, after the stirring at room 30 minutes, and add and splash into 0.67ml cyclopropyl bromination thing, refluxed cooling 8 hours, with methylene dichloride diluting reaction medium, and pour on ice.
Dry evaporation organic phase, oily matter, purifying on silicagel column then, (40: 1V/V) mixture is made eluent with hexanaphthene and ethyl acetate.Yield: 57%4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-Jia Jibianji)-N-(encircling third methyl) amino] proton NMR spectrum of thiazole is illustrated in the Table VII.Embodiment 42
4-(2,4 dichloro benzene base)-2-{N-[cyclopropyl (4-imidazolyl) methyl]-the N-third hydrogen base }-5-methylthiazol steps A
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopropyl (1-trityl-4-imidazolyl) methyl]-N-third amino } thiazole
According to embodiment 1 described method, from N-[cyclopropyl (1-trityl-4-imidazolyl) methyl]-N-propyl group thiocarbamide (compound 86) and 2-bromo-1-(2,4 dichloro benzene base)-1-acetone (compound 15) makes this title compound.Step B
45ml 2N hydrochloric acid is added in the preceding step gained 3g product that is dissolved in the 45ml acetone, after the ambient temperature overnight, boil off acetone, wash the water that stays, and then wash with sodium bicarbonate with ether, the throw out that generates with the 100ml ethyl acetate extraction three times, wash organic phase with saturated aqueous sodium chloride, dry on anhydrous sodium sulphate, vacuum-evaporation, get white powdery 4-(2,4 dichloro benzene base)-5-methyl-2-{ N-[cyclopropyl (4-imidazolyl) methyl]-N-third amino } thiazole.Yield: 90% fusing point: the proton NMR spectrum of 83 ℃ of these products is illustrated in the Table VII.Embodiment 43
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[1-(4-imidazolyl) ethyl]-N-third amino } thiazole
The preparation of this product is according to embodiment 42 described methods, and with the N-[1-in the steps A (1-trityl-4-imidazolyl) ethyl]-N-propyl group thiocarbamide obtains as (compound 87) thiourea derivative, and the proton NMR spectrum of this product is illustrated in the Table VII.Embodiment 44
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopropyl (1-benzyl-4-imidazolyl) methyl]-N-third amino } thiazole
320mg salt of wormwood is added in the compound of the 492g embodiment 42 that is dissolved in the 10ml dimethyl formamide, slowly adds the 0.12ml benzyl chloride that is dissolved in the 1ml dimethyl formamide at 0 ℃ then, kept 3 hours near 60 ℃, 80 ℃ 3 hours, add water and generate precipitation.Use ethyl acetate extraction, with saturated aqueous sodium chloride Xian organic phase, be evaporated to driedly, at the enterprising circumstances in which people get things ready for a trip spectrometry of silicagel column purifying residue, (2: 1V/V) mixture is made eluent with hexanaphthene and ethyl acetate.Yield: 67%
Add and be dissolved in an amount of 0.1N hydrochloric acid of Virahol, the dihydrochloride that generation is corresponding.Fusing point: 115 ℃
4-(2,4 dichloro benzene base)-5-methyl-2-{ N-[cyclopropyl (1-benzyl-4-imidazolyl) methyl]-N-third amino } the thiazole proton NMR spectrum is illustrated in the Table VII.Embodiment 45
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopropyl (1-methyl-4-imidazolyl) methyl]-N-third amino } thiazole
The 570mg powdered potassium hydroxide is added in the compound of the 856mg embodiment 42 that is dissolved in the 10ml acetone.Stirred 5 minutes, add the 0.14ml methyl-iodide then, in room temperature after 15 minutes, with 100ml methylene dichloride diluted reaction mixture, water and saturated sodium chloride aqueous solution are washed, and dry organic phase on sodium sulfate is evaporated to dried, chromatography purification residue on silicagel column is made eluent with the mixture of hexanaphthene and ethyl acetate (1: 1 V/V).
Like this, separate 4-(2, the 4-dichlorophenyl)-5-methyl-2-{N-[cyclopropyl (1-methyl-4-imidazolyl) methyl]-N-third amino } thiazole and 4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopropyl (3-methyl-4-imidazolyl) methyl]-N-third amino } thiazole (37: 63) yield: 33%.Embodiment 46
5-bromo-4-(2,4 dichloro benzene base)-2-{N-[propyl group-N-[1-(4-pyridyl) ethyl] amino } thiazole
1g4-(2,4 dichloro benzene base)-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } compound of thiazole embodiment 25 is dissolved in the 20ml methylene dichloride, adds the 0.15ml bromine, stirring is spent the night, be evaporated to driedly, residue is dissolved in a spot of Virahol, use ether sedimentation.Filter, wash, be dissolved in then in 5% wet chemical, use ethyl acetate extraction with ether, dry on sal epsom, be evaporated to dried, the oily product that must be desired, yield: 80%.5-bromo-4-(2,4 dichloro benzene base)-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } proton NMR spectrum of thiazole is illustrated in the Table VII.Embodiment 47
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(two rings, third methyl)-N-third amino] thiazole
In 1g N-in being dissolved in the 25ml ethanol solution (two rings, third methyl)-N-propyl group thiocarbamide (compound 88), add the 0.54ml triethylamine, slowly add 1g 2-bromo-1-(2,4 dichloro benzene base)-1-acetone (compound 15) then.Reflux is evaporated to dried after 2 hours in ethanol.Residue is dissolved in the methylene dichloride, washes with water till bromide anion is all removed.Dry organic phase on anhydrous sodium sulphate, and be evaporated to dried, purifying residue on silicagel column, with hexanaphthene and ethyl acetate (20: 1V/V) mixture is made eluent, the oily product that be desired.Yield 88% proton NMR spectrum is listed in the Table VII.
In order to obtain corresponding vitriol, the 1M vitriolic ethanolic soln of appropriate amount is added in this alkali.Fusing point: 140 ℃ of embodiment 48
4-(2,4 dichloro benzene base)-5-methyl-2-{N-[cyclopentyl (cyclopropyl) methyl]-N-third amino } thiazole
It is with embodiment 47 described methods, with N-[cyclopentyl (cyclopropyl) methyl that this compound makes]-N-propyl group thiocarbamide (compound 90) makes thiourea derivative.Purifying on silicagel column is with hexanaphthene and ethyl acetate (10: 1V/V) make eluent.Yield: 95% proton NMR spectrum is listed in the Table VII.Embodiment 49
4-(2,4 dichloro benzene base)-5-formyl radical-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } thiazole
In flask at the bottom of the 3 ml dimethyl formamides adding 100ml garden.Be chilled to-30 ℃, splash into the 0.45ml oxalyl chloride, stir at 0 ℃ and heated up then in 30 minutes, add 0.5g embodiment 25 compounds, stirred 6 hours, standing over night adds water and alkalizes with the 1N sodium hydroxide solution.What filtration generated precipitates gummyly.Be dissolved in a small amount of ether and add hexane till generating light color, staticly settle thing, filter, wash, get the orange crystalloid product of institute's desire with hexane.Yield: 75% fusing point; 114 ℃ of 4-(2,4 dichloro benzene base)-5-formyl radical-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } proton NMR spectrum of thiazole lists in the Table VII.Embodiment 50
4-(2,4 dichloro benzene base)-5-methylol-2-(N-propyl group-N-[1-(4-pyridyl) ethyl] amino } thiazole
Cooling contains the 20ml absolute methanol solution of 1.1g embodiment 49 compounds on ice bath, adds the 0.2g sodium borohydride on a small quantity, room temperature reaction, boil off solvent, use the ethyl acetate extraction residue, dry organic phase on anhydrous sodium sulphate, be evaporated to driedly, and residue be dissolved in the ether.
With the hexane precipitation, get orange powder product that shape is desired.Yield: 72% fusing point: the proton NMR spectrum of 113 ℃ of these products is listed in the Table VII.Embodiment 51
4-(2,4 dichloro benzene base)-5-methyl-2-{N-(2-propenyl)-N-[1-(4-pyridyl) ethyl] amino } thiazole
The method of pressing embodiment 1 in three-necked flask under argon gas is from N-[1-(4-pyridyl) ethyl] the 2-bromo-1-(2 of thiocarbamide, the 4-dichlorophenyl)-and 2.0g 4-(2,4 dichloro benzene base)-5-methyl-2-{N-[1-(4-pyridyl) ethyl of 1-acetone (compound 15) preparation] amino } thiazole is dissolved in the 20ml anhydrous tetrahydro furan.
Add the 0.4g lithium amide at 50 ℃, and stirred 1 hour, add the 0.43g allyl bromide 98, in 60 ℃ of heating 48 hours.
Be evaporated to dried, add 10ml 10% aqueous sodium hydroxide solution, use ethyl acetate extraction, dry organic phase on anhydrous sodium sulphate, be evaporated to dried, with ethyl acetate and hexane (75: mixture 25V/V) is made eluent purifying residue, desire the oily product yield: 20% proton NMR spectrum is listed in the Table VII.
In order to obtain 4-(2,4 dichloro benzene base)-5-methyl-2-{ N-(2-propenyl)-N-[1-(4-pyridyl) ethyl] amino } oxalate of thiazole, the alkali of 0.4g is dissolved in a small amount of Virahol, add and give the 0.18g oxalic acid that is dissolved in Virahol earlier.
Be evaporated to dried, earlier with Virahol and ether (50: 50V/V) mixture, use the Virahol recrystallization then.Fusing point: 150 ℃ of embodiment 52
4-(4-chloro-2-hydroxyphenyl)-5-methyl-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } thiazole
With 700mg 4-(4-chloro-2-methoxyphenyl)-5-methyl-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } embodiment 22 compounds of thiazole are dissolved in the 30ml concentrated hydrobromic acid and refluxed 24 hours.Be evaporated to driedly, residue is dissolved in the salt of wormwood saturated aqueous solution, use dichloromethane extraction, steam and remove organic solvent, purifying residue on silica gel chromatography, (9: 1V/V) mixture is made eluent, the oily product that must be desired with ethyl acetate and methyl alcohol.Yield: the proton NMR spectrum of 67% this embodiment compound is listed in the Table VII.Embodiment 53
4-(2-chloro-4-hydroxyphenyl)-5-methyl-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } thiazole
According to embodiment 52 described methods, from embodiment 27, obtain this title compound.4-(2-chloro-4-hydroxyphenyl)-5-methyl-2-{N-propyl group-N-[1-(4-pyridyl) ethyl] amino } proton NMR spectrum of thiazole lists in the Table VII.Embodiment 54 to 88
According to embodiment 1 described method,, can obtain embodiment 54 to 87 compounds with suitable martonite and thiourea derivative.
Their spectral quality is listed in the Table VII.Embodiment 89
5-bromo-4-(2,4 dichloro benzene base)-2-[N-(α-cyclopropyl benzyl)-N-third amino] thiazole
According to embodiment 46 described methods, and from 4-(2,4 dichloro benzene base)-2-[N-(α-cyclopropyl benzyl)-N-third amino] can prepare this title compound thiazole embodiment 82 compounds.Proton NMR spectrum is listed in the Table VII.Embodiment 90
4-(2,4 dichloro benzene base)-5-iodo-2-[N-(α-cyclopropyl benzyl)-N-third amino] thiazole
With 496mg 5-bromo-4-(2, the 4-dichlorophenyl)-and 2-[N-(α-cyclopropyl benzyl)-N-third amino] thiazole embodiment 89 compounds are dissolved in the 20ml ether, cool off this solution to-70 ℃, slowly add 0.8ml tert-butyl lithium (1.5N is in pentane) solution then, additional adding is dissolved in the iodine of the 305mg in the 20ml tetrahydrofuran (THF), and temperature is slowly gone up to 0 ℃.Use the saturated aqueous sodium chloride hydrolysis, wash with thiosulfate solution.
With embodiment 1 described method purifying, get the product of being desired.4-(2,4 dichloro benzene base)-5-iodo-2-[N-(α-ring third benzyl)-N-third amino] proton NMR spectrum of thiazole lists in the Table VII.Embodiment 91
4-(2-chloro-4-iodophenyl)-5-methyl-2-[N-(α-ring third benzyl)-N-third amino] thiazole
According to embodiment 1 described method, prepare this title compound from N-(α-cyclopropyl benzyl)-N-propyl group thiocarbamide (compound 75) and 2-bromo-1-(2-chloro-4-iodophenyl)-1-acetone (compound 18).The proton NMR spectrum of this compound is listed in the Table VII.Embodiment 92
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(2,2-two cyclopropyl ethyls)-N-third amino] thiazole
According to embodiment 1 described method, make this title compound from 2-bromo-1-(2,4 dichloro benzene base)-1-acetone (compound 15) and N-(2,2-two cyclopropyl ethyls)-N-propyl group thiocarbamide (compound 115).Fusing point: gumminess.Proton NMR spectrum (solvent C DCl 3): 0.0-0.7ppm, m, 11H; 0.9ppm, m, 3H; 1,4-1.9ppm, m, 2H; 2.10ppm, s, 3H; 3,3-3.5ppm, m, 4H; 7.1-7.4ppm, m, 3H. embodiment 93
4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl)-N-third amino] thiazole (+) isomer and 4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl)-N-third amino] thiazole (-) isomer
According to two kinds of methods, can obtain 4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl)-N-third amino] two kinds of steric isomers of thiazole (embodiment 1 compound)
Method A steps A α-cyclopropyl benzyl amine
Under 50 ℃ of argon gas in the presence of the 4_ molecular sieve, with the 2000ml methanol solution of 100g cyclopropyl benzophenone with give first exsiccant 500g ammonium acetate and 50g sodium cyanoborohydride and stirred 4 days, after the cooling, filter molecular sieve, add concentrated hydrochloric acid to pH be 2, vacuum evaporated solution is to doing, water-soluble residue, with ethyl acetate wash water phase, pH is more than 10 for the alkalization of enriching potassium hydroxide solution, use the dichloromethane extraction secondary, wash with saturated sodium-chloride water solution, dry on anhydrous magnesium sulfate, vacuum concentration gets α-cyclopropyl benzylamine, needn't be further purified, be directly used in next step.Yield: 76% step B α-cyclopropyl benzylamine (+) isomer and α-cyclopropyl benzylamine (-) isomer
80.6g L (+) tartrate is added in the 275ml dehydrated alcohol refluxes, the 79g α-cyclopropyl benzylamine of step gained above dripping then.After being added dropwise to complete, slowly cooling off reaction medium, and get crystal.These crystal 5s of recrystallization in dehydrated alcohol.With the polarimetry purity of Mosher ' s reagent by gas chromatography determination gained amine.α-cyclopropyl benzylamine (+) isomer tartrate form, polarimetry purity is greater than 96% yield: 25% fusing point: 150 ℃
Figure C9310943800671
Solubilising in water, dichloromethane extraction is used in the solution alkalization, after dry on the anhydrous magnesium sulfate and vacuum-evaporation, can obtain α-cyclopropyl benzylamine (+) isomer from salt.
Merge ethanolic soln from top folding divides, and be evaporated to driedly, residue is water-soluble, and dichloromethane extraction use in alkalization, and drying is evaporated to dried on anhydrous magnesium sulfate.With D (-) tartrate salify, with top described salt action and method for splitting, in ethanol behind 4 recrystallizations, the tartrate of α-cyclopropyl benzylamine (-) isomer, polarimetry purity is greater than 96%.Yield: 20% fusing point: 151 ℃ Step C4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl) amino] thiazole (-) isomer and 4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl) amino] thiazole (+) isomer
With the described method of preparation XV, make amine with α-cyclopropyl benzylamine (+) isomer, get N-(α-cyclopropyl benzyl) thiocarbamide (+) isomer, then according to the method for embodiment 1, with N-(α-cyclopropyl benzyl) thiocarbamide (+) isomeric compound and 2-bromo-1-(2, the 4-dichlorophenyl)-1-acetone (compound 15) reaction, get 4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl) amino] thiazole (-) isomer.Total recovery: 62%
Figure C9310943800682
According to method recited above, make initial amine with α-cyclopropyl benzylamine (-) isomer, preparation 4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl) amino] thiazole (+) isomer.Step D
With 1.18g 4-(2, the 4-dichlorophenyl)-and 5-methyl-2-[N-(α-cyclopropyl benzyl) amino] thiazole (-) isomer is dissolved in the 35ml anhydrous dimethyl formamide, 0 ℃ added the 145mg sodium hydride, adds the 370mg propyl bromide after gas stops, in 75 ℃ of heating 2 hours 30 minutes.Evaporation is as for, water hydrolysis.Use the ethyl acetate extraction water, with the organic phase that saturated sodium-chloride water solution is washed gained, dry on anhydrous magnesium sulfate, vacuum-evaporation gets residue, and purifying on the silicagel column is made eluent with hexanaphthene and ethyl acetate (20:1V/V) mixture.
Get gummy 4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl)-N-amino] thiazole (-) isomer product.
Figure C9310943800691
From this alkali, and can obtain following salt :-hydrochloride: fusing point: 66.5 ℃ with the suitable acid that is dissolved in the ethanol
Figure C9310943800693
-right-tosylate: fusing point: 72 ℃
According to method recited above, with 4-(2, the 4-dichlorophenyl)-5-methyl-2-[N-(α-cyclopropyl benzyl) amino] thiazole (+) isomer makes 4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl)-N-third amino] thiazole (+) isomer
With 4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl)-N-third amino] the methanol solution reaction of thiazole (+) isomer and hydrochloric acid, make corresponding hydrochloride.Fusing point: 71 ℃
Figure C9310943800695
Method B steps A α-cyclopropyl benzylamine (+) isomer and α-cyclopropyl benzyl (-) isomer.
According to Org.Synth.Coll.VolII, P.70, AH, Blatt, J.Willey and Sons Inc.Edt.N.Y., London.Sydney.Cipyright 1943 described methods, preparation (E, Z)-(cyclopropyl-phenyl ketoxime)
The gained mixture contains 76%E isomer and 24%Z isomer thus.In the methyl alcohol recrystallization several times, or according to the isomerization in acid medium of following described method.
(E Z)-(cyclopropyl-phenyl ketoxime) is dissolved in the 20ml anhydrous diethyl ether, and saturated with gas chlorination hydrogen 2g.Filter the gained throw out, add 50ml 10%K 2CO 3The aqueous solution.This solid dichloromethane extraction.Organic phase washes with water, and is dry on anhydrous magnesium sulfate, evaporation as for, (E)-(cyclopropyl-phenyl ketoxime).Purifying: 98%
To be dissolved in the 1.61g oxime of gained like this in the 10ml anhydrous dimethyl formamide, be added in the 10ml anhydrous dimethyl formamide solution that contains 276mg hydride.After room temperature is stirred 1 hour, add the 0.75ml methyl-iodide, stir after 4 hours, on ice the reaction medium impouring.Use ethyl acetate extraction, dry vacuum-evaporation, purifying on the silicagel column, (40: 1V/V) mixture is made eluent with hexanaphthene and ethyl acetate, get (E)-(cyclopropyl-phenyl ketoxime) methyl ether, in 385mg norephedrine (-) isomer that is dissolved in the 5ml anhydrous tetrahydro furan, at-30 ℃, add 8.6ml 1M borane-tetrahydrofuran (THF) mixture, thus 300mg (E)-(cyclopropyl-phenyl ketoxime) methyl ether is dissolved in the 3ml anhydrous tetrahydro furan, reflux after 2 hours 30 minutes, add 10ml water and 10ml 20% sodium hydroxide at 0 ℃ then, refluxed 1 hour 30 minutes.After the cooling, use dichloromethane extraction, the organic phase drying is evaporated to driedly, and residue is dissolved in excessive methanol, refluxes 5 hours, be evaporated to dried, purifying on silicagel column, (96: 4V/V) mixture is made eluent with methylene dichloride and methyl alcohol.
Thus α-cyclopropyl benzylamine (+) isomer, polarimetry purity is greater than 90%, yield: 40%
According to above-mentioned said method, do the chirality agent in reduction (E)-(cyclopropyl phenyl ketoxime) methyl ether with falling fiber crops steaming alkali (+) isomer, obtain α-cyclopropyl benzyl (-) isomer step B and C
With method A step C and the described method of D, get 4-(2, the 4-dichlorophenyl)-and 5-methyl-2-[N-(α-cyclopropyl benzyl)-N-third amino] thiazole (+) isomer and 4-(2,4 dichloro benzene base)-5-methyl-2-[N-(α-cyclopropyl benzyl)-N-third amino] thiazole (-) isomer.
Table VII
Figure C9310943800722
Table VII (continuous 1)
Figure C9310943800731
Table VII (continuous 2)
Figure C9310943800741
Table VII (continuous 3)
Figure C9310943800751
Table VII (continuous 4)
Figure C9310943800761
Table VII (continuous 5)
Figure C9310943800771
Table VII (continuous 6)
Figure C9310943800781
Table VII (continuous 7)
Figure C9310943800791
Table VII (continuous 8)
Figure C9310943800801
Table VII (continuous 9)
Figure C9310943800811
Table VII (continuous 10)
Figure C9310943800821
Table VII (continuous 11)
Figure C9310943800831
Table VII (continuous 12)
Table VII (continuous 13)
Table VII (continuous 14)
Table VII (continuous 15)
Table VII (continuous 16)
Figure C9310943800881
Table VII (continuous 17)
Figure C9310943800891
Table VII (continuous 18)
Pharmaceutical preparation embodiment 94
4-(2,4 dichloro benzene base)-2-[N-(bicyclic methyl propyl)-N-third amino that contains 0.20mg dosage]-hard gelatin capsule of 5-methylthiazol vitriol
N-(2,4 dichloro benzene base)-2-[N-(two
The cyclopropyl methyl)-N-third amino]-the 5-methyl thiazolium
Azoles vitriol 20mg
W-Gum 15mg
Lactose 25mg
Each numbering 3 of talcum powder 5mg is hard gelatin capsules.

Claims (10)

1. compound of Formula I, the steric isomer that they are possible and they and mineral acid or organic acid additive salt;
Figure C9310943800021
Wherein-R 1Expression A 1Group or formula A 2Group; Its Chinese style X, Y and Z can be identical or different, and represent hydrogen atom, halogen atom separately, contain the alkoxyl group of 1-5 carbon atom, the alkyl that contains 1-5 carbon atom, hydroxyl, or R 1Representative formula A 2Group -R 2Expression hydrogen atom, halogen atom, the alkyl that contains 1-5 carbon atom, methylol or formyl radical ,-R 3Expression contains the alkyl of 1-5 carbon atom, the cycloalkyl that contains 3-8 carbon atom, the alkenyl that contains 2-6 carbon atom, the cycloalkylalkyl that contains 4-8 carbon atom or phenyl ,-R 4The expression hydrogen atom ,-R 5Expression contain the alkyl of 1-5 carbon atom, arbitrarily by the cycloalkyl of 3-8 carbon atom of the alkyl replacement that contains 1-5 carbon atom, contain 4-8 carbon atom straight chain cycloalkylalkyl, contain the alkenyl of 2-6 carbon atom or the group of Formula B
Figure C9310943800031
Its Chinese style p equals 0 or 1 ,-R 6Expression phenyl, pyridyl, imidazolyl or thienyl, group wherein can be arbitrarily replaced by 1 group by p among one or more halogen atoms, the alkoxyl group that contains 1-5 carbon atom, the alkyl that contains 1-5 carbon atom, trifluoromethyl, methylthio group or the formula B, perhaps expression contains 3-8 carbon atom and any by the cycloalkyl that alkyl replaced that contains 1-5 carbon atom,-m can represent 0 or 1, and n represents 0.
2. the formula I compound of claim 1, their steric isomer and they and mineral acid or organic acid additive salt, wherein :-R 1Expression A 1Group ,-R 2Expression halogen atom or contain the alkyl of 1-5 carbon atom ,-R 3Expression contain 1-5 carbon atom alkyl, contain the cycloalkyl of 3-8 carbon atom or contain the alkenyl of 2-6 carbon atom ,-R 5Expression contain 1-5 carbon atom alkyl, contain 3-8 carbon atom and can be contained arbitrarily 1-5 carbon atom alkyl replacement cycloalkyl or contain the straight chain cycloalkyl of 4-8 carbon atom, and-R 4, R 6, m and n be identical with the definition of claim 1 general formula I.
According to claim 1 corresponding to general formula I AFormula I compound, their steric isomer and they and mineral acid or organic acid additive salt, Wherein :-Y and Z are identical with the general formula I definition of claim 1 ,-R 5The alkyl of 1-5 carbon atom of expression or contain 3-8 carbon atom and any by the alkyl replacement that contains 1-5 carbon atom cycloalkyl or contain the straight chain cycloalkylalkyl of 4-8 carbon atom ,-R 6Expression phenyl or pyridyl, they can be replaced by one or more halogen atoms, the alkoxyl group that contains 1-5 carbon atom, the alkyl that contains 1-5 carbon atom, trifluoromethyl or methylthio group arbitrarily, any by containing the imidazolyl that 1-5 carbon atom alkyl replaces, the cycloalkyl that perhaps contains 3-8 carbon atom and can be replaced by the alkyl of 1-5 carbon atom arbitrarily.
4. according to claim 1 be corresponding to the compound of general formula I: 4-(2,4 dichloro benzene base)-5-methyl-2-{N-cyclopropyl (4-pyridyl) methyl)-N-third amino thiazole and with mineral acid or organic acid additive salt.
5. according to claim 1 be: 4-(2,4 dichloro benzene base)-5-methyl-2-{N-(α-cyclopropyl benzyl)-N-third amino corresponding to the compound of general formula I } thiazole and with mineral acid or organic acid additive salt.
6. according to claim 1 be corresponding to the compound of general formula I: 4-(2,4 dichloro benzene base)-5-methyl-2-(N-(bicyclic methyl propyl)-N-third amino) thiazole and with mineral acid or organic acid additive salt.
7. according to claim 1 be: 4-(2,4 dichloro benzene base)-5-methyl-2-{N-(cyclopentyl (cyclopropyl) methyl)-N-third amino corresponding to the compound of general formula I } thiazole and with mineral acid or organic acid additive salt.
8. according to claim 1 be corresponding to the compound of general formula I: 4-(2-chloro-4-aminomethyl phenyl)-5-methyl-2-(N-(bicyclic methyl propyl)-N-third amino) thiazole and with mineral acid or organic acid additive salt.
9. preparation is the alpha-halogen carbonyl derivative of general formula I I according to the method for claim 1 compound of Formula I: R wherein 1Definition with identical according to claim 1 general formula I, R 2' expression hydrogen atom or contain the alkyl group of 1-5 carbon atom, and Hal represents halogen atom, perhaps the thiocarbamide with formula III reacts: R wherein 3, R 4, R 5With n with identical according to definition in claim 1 general formula I, and R 6' and according to R in claim 1 general formula I 6Define identical, except when R 6When containing the functional group for active N atom, at this moment corresponding to R 6R 6' represent that the wherein said active group H of group atom can the protecting group of anti-hydrolysis be replaced in alkaline medium,
To form general formula I ' compound:
Figure C9310943800062
Wherein-R 1, R 3, R 4, R 5, m and n be with identical according to the definition in claim 1 general formula I ,-R 2' identical with definition among the general formula I I, and-R 6' identical with definition in the general formula III, perhaps with formula III AThiocarbamide reaction
Figure C9310943800063
R wherein 4, R 5, m and n definition with according to identical in claim 1 general formula I, and R 6' identical with the general formula III definition,
To form general formula I V compound: R wherein 1, R 4, R 5, m and n be with identical according to the definition of claim 1 general formula I, R 2' identical with general formula I I definition, and R 6' identical with the general formula III definition,
Halide reaction with formula V
Hal-R 3(V) wherein Hal represents halogen atom, and R 3With identical according to the definition of claim 1 general formula I,
To form general formula I ' compound, R then-wherein 2' expression hydrogen atom formula I ' compound
* or with halogen react, form R 2The compound of Formula I according to claim 1 of expression halogen atom then, is worked as R 2During the expression bromine atoms, can form the compound of Formula I that R2 represents this halogen with another halogen reaction,
* or with oxalyl chloride react, to prepare wherein R 2Be the compound of Formula I as claimed in claim 1 of formyl group, it can obtain wherein R through reduction reaction again 2Be the compound of Formula I as claimed in claim 1 of methylol, perhaps-general formula I ' compound, wherein R 6' expression has the radicals R of protecting group for active N atom 6, make it to carry out acid hydrolysis, obtain wherein R 6Contain primary amine or secondary amine group compound of Formula I as claimed in claim 1, and, if be fit to, compound of Formula I according to claim 1
Can then be separated into their possible steric isomers and/or use and form corresponding salt with mineral acid or organic acid salinization.
10. pharmaceutical composition, it contains the compound according to claim 1-8 of the alkali form or the organic acid salt form of significant quantity, and a kind of medicinal nontoxic inertia excipient.
CN93109438A 1992-06-24 1993-06-23 Branched alkylamino derivatives of thiazole, processes for preparing them and pharmaceutical compositions containing them Expired - Fee Related CN1035552C (en)

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EP0576350A1 (en) 1993-12-29
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PL299445A1 (en) 1994-01-24
PH30921A (en) 1997-12-23
EP0576350B1 (en) 1997-10-29
US5464847A (en) 1995-11-07
FR2692893B1 (en) 1994-09-02
HUT66384A (en) 1994-11-28
SI9300337A (en) 1994-03-31
CZ125293A3 (en) 1994-01-19
IL106088A (en) 1997-09-30
NO303118B1 (en) 1998-06-02
NO932319L (en) 1993-12-27
TW256834B (en) 1995-09-11
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IS4040A (en) 1993-12-25
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